The hormone angiotensin II is recognized as one of the most potent vasopressor agents that produces hypertension in mammals. The action of the enzyme renin on the plasma protein substrate angiotensinogen results in production of the inactive decapeptide angiotensin I, which upon conversion by the nonselective angiotensin converting enzyme (ACE) provides angiotensin II, the active hormone. See e.g. Regoli et al. , Pharm. Rev. 26: 69 (1974) .
U. S. Pat. No. 5,073,566 and U. S. patent application Ser. No. 07/892,867 disclose potent and effective 1,3 -imidazoles, as angiotensin II antagonists of the Formula I: ##STR3##
These compounds may exist in various stereoisomeric forms. In particular, the compounds exist as enantiomers due to the chiral carbon atom to which the imidazole, R.sub.1, and R.sub.2 are attached. U.S. Pat. No. 5,073,566 and U.S. patent application Ser. No. 07/892,867 disclose the separation of the enantiomers by chromatographic separation of an intermediate or the final product. The obvious shortcomings of chromatographic separation are inefficiency and expense. The separation is particularly inefficient if the separation is performed as the final step where one-half of the final product may be discarded as the undesired enantiomer.
The present invention provides compounds that are useful as intermediates in the preparation of the substantially pure (R) enantiomer of angiotensin II antagonists of Formula I.
The compounds of the present invention are prepared by a process generally characterized as an optical resolution. See Jacques, et al., Enantiomers, Racemates, and Resolutions (John Wiley and Sons 1981). Unfortunately, when attempting to apply these general teachings to efficiently separate enantiomers, it is impossible to determine what conditions or resolving agents will be successful. In the present invention, resolving agents such as brucine, ephedrine, quinidine, cinchonine, and quinine produced unacceptable mixtures of diastereoisomeric salts. Thus, the present invention further provides a process of preparing the compounds of the present invention by disclosing a remarkably effective resolving agent that selectively crystallizes the substantially pure enantiomer.